The objective of this work is to study the role of thyroid hormone binding proteins in mediating the toxic effects of certain halogenated aromatic hydrocarbons of environmental importance. Current interest is in the binding proteins specific for thyroxine (T4). Prealbumin (TBPA) is a major thyroxine binding protein in blood which has been proposed as a model for the thyroxine nuclear receptor in tissue. Molecular interactions of TBPA with the dioxins, furans and polychlorinated biphenyls (PCBs) have been studied with use of computer graphics and predictions made regarding relative binding affinities for such structures. These modeling predictions were tested by experimentally measuring the binding affinities of soluble derivatives of those structures, and the results are in good agreement with prediction. The binding model can account for the requirements for lateral halogens and for a linear and symmetrical molecular shape in toxicity. Similar results were obtained in studies investigating the inhibitory potency of outer (phenolic) ring deiodination of reverse triiodothyronine (r-T3 5'-deiodinase) in microsomal fractions of rat liver in vitro for which TBPA served as an active site model. The thyroxine nuclear protein solubilized from rat liver tissue also showed competitive binding interactions with similar structural specificity but with the additional requirement of a preference for structures which were planar and highly polarizable. A soluble dioxin approximate isostere shows a remarkably high affinity for the nuclear receptor. Thus the nuclear receptor affinity has the expected sensitivity for possible involvement in toxicity. Dose-dependent regulation (increase) of the T4 nuclear receptor number by dioxin was demonstrated and suggest a possible mechanism for potent and persistent expression of thyroid hormone activity which could result in toxicity.